1. Field of the Invention
The current invention concerns a method for improvement of tolerance for therapeutically effective agents delivered by inhalation said method comprising a pretreatment step utilizing a composition comprising a lidocaine or lidocaine-like compound, said composition delivered by nebulization using an electronic nebulizer. In particular, the invention concerns a method for improvement of tolerance for a primary therapeutically effective agent delivered by inhalation, said method comprising a pretreatment of a patient with a nebulized lidocaine or lidocaine-like compound administered immediately or up to about thirty minutes before administration of the primary therapeutically effective agent. The pretreatment of the patient with the nebulized lidocaine or lidocaine-like compounds improves airway tolerance and deposition of the therapeutically effective agent in the lungs and makes such deposition more safe, efficacious, controllable and predictable. The pretreatment step may also include oral or systemic administration of lidocaine or lidocaine-like compounds prior to administration of the primary therapeutic agent. The method of the invention is especially useful for enhancement of deposition of immunosuppressive agents in the lung(s) of lung transplant patients.
2. Background and Related Disclosures
A recent trend in medical drug delivery is directed toward targeted drug delivery to a region where the drug treatment is most efficacious, with a specific aim to avoid, if possible, the adverse reactions often observed with oral or other systemic drug delivery. Thus all diseases which affect lungs, currently treated with systemically administered drugs, would be preferentially treated with an aerosolized drug in an aerosol having specific parameters allowing a deposition of such drug in the lung region where the treatment is needed. However, aerosolized drug delivery may also be conveniently used for systemic administration of drugs, such as, for example, insulin, morphine, fentanyl and growth hormone, among others. The aerosolization of the drug and its administration through the lungs thus may substitute or complement the systemic drug delivery.
When the aerosolization is contemplated as a substitute drug delivery, the aerosol must be prepared in such a way that the aerosolized particles are predominantly deposited in the lung region where it is most efficacious and such deposition to other regions or to the upper respiratory airways, such as to the oropharyngeal area, is minimized.
In this regard, the lungs are divided into three regions. The upper lung covers the pharyngeal and tracheal region. The central lung covers lower trachea, bronchi and bronchiolar branches. The lower lung covers bronchioli and alveoli. Drugs administered via aerosol intended for delivery of the drugs to the lungs are administered in the aerosol directed to the central or lower lungs. Drugs administered via aerosol intended for systemic absorption are administered in the aerosol directed to the lower lungs, particularly to the deposition in alveoli from where the drug is absorbed into the general circulation. Additionally, the deposition in the mouth and nose, that is in the oropharyngeal area, must be avoided.
Depending on the region where the drug should be deposited, the prepared aerosol needs to have certain properties, particularly it needs to have a spectrum of particle sizes which reaches that particular region and which is preferably not deposited in other lung regions.
Aerosolized drug delivery provides certain advantages, such as safety and efficacy, compared to the systemic drug delivery. For example, since the drug is delivered directly to the target region, the amount of the drug needed to assert its therapeutic effect is lower than the systemic dose because the systemic dose must account for delivery of the drug throughout the whole body rather than only to the organ where the treatment is needed. Additionally, since the systemic delivery is avoided, there are none or lesser undesirable secondary effects. Finally, in cases where the aerosolized delivery substitutes oral delivery, there is a sparing effect for gastrointestinal tract, or circumvention of the intravenous route.
Despite all these advantages, up-to-date attempts to substitute the systemic treatments with aerosolized drug delivery has met with only partial success because some of the drugs, particularly more potent drugs such as for example, certain immunosuppressants, antibiotics and antifungals, are not well tolerated by lungs and such aerosolized delivery is thus limited.
Thus it would be desirable to have available a method and a means to improve delivery of and tolerance for these agents by inhalation.
A pretreatment with a nominal doses of the aerosolized lidocaine or lidocaine-like compounds prepared as a targeted aerosol and delivered by electronic nebulizer has been now found to improve such tolerance to the aerosolized drug delivery.
Lidocaine is a local and regional anesthetic currently approved for administration either as an injectable anesthetic for treatment of, for example, peripheral nerve, lumbar or caudal epidural block, as an intravenous infusion as an antiarrhythmic agent or in topical preparations for dermal, ocular and mucosal numbing (O'Neil M J. et al., Eds., The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals, 13th ed., Whitehouse Station, N.J.: Merck & Co., Inc. (2001).
Topical lidocaine has been previously also used prior to bronchoscopy to reduce airway reactivity and has been recommended as an aerosol for intractable cough and asthmatic tussive attacks (Chest, 105(5):1592-3 (1994), JAMA, 252(17):2456-7 (1984), Anaesthesia, 49(2):182 (1994) and Chest, 69(6):747-51 (1976)).
Adverse events related to lidocaine are not uncommon and cases of anaphylactic reactions and acute respiratory distress syndrome (ARDS) upon pulmonary application have been reported, for example, in Chest, 81(5) :644-5 (1982), Chest, 83(3) :585 (1983) and Chest, 83(6):933-4 (1983).
Adverse events associated with aerosolized lidocaine include numbing of lips, tongue and oral mucosa, and impaired gag reflex (Am. Rev. Respir. Dis., 122(6):823-8 (1980), Eur. J. Anaesthesiol., 17(11) :672-9 (2000) and JAMA, 236(6) :562 (1976) have been described.
The chronic topical application of aerosolized lidocaine to the airways used in previous studies was not associated with systemic toxicity (Mayo Clin. Proc., 71(4):361-8 (1996) and Ann. Allergy Asthma Immunol., 82(1):29-32 (1991).
The efficacy of chronic nebulized lidocaine was evaluated in studies in groups of adult and pediatric subjects with severe asthma at the Mayo Clinic in Rochester, Minn. These studies demonstrated a steroid-sparing effect and significant reduction in hospitalizations. No drug related serious adverse experiences were reported and the majority of subjects with steroid dependent asthma were at least partially weaned from oral corticosteroids (Int. J. Tuberc. Lung Dis., 1:5, Suppl 1:S 32 (1997)).
In addition, lidocaine aerosol application to the airways attenuated the bronchoconstriction reflex provoked by inhalation challenge with histamine and methacholine, and challenges with hyperosmolar and hypoosmolar solutions, such as water. Am. J. Respir. Crit. Care Med., 154(4 Pt 1):885-8 (1996) and Chest, 72(4):429-38 (1977).
Nonetheless, the administration of aerosolized lidocaine is not without problems and complications. For example, upon aerosolization of 100 mg dose of lidocaine administered in 2.5 ml of a 40 mg/ml solution using the PARI LC PLUS™ nebulizer, oral numbing of lips, tongue and mucosa, along with an impaired gag reflex occurred for approximately 15 minutes following the inhalation of lidocaine (Am. J. Respir. Crit. Care Med., 163 (5):A83 (2001). To overcome these reactions, it has been recommended that treated subjects should not eat or drink for one hour after aerosol treatment. Under this regime, lesser adverse events related to impaired swallowing or reflux have been reported.
In recent years, use of lidocaine was proposed also for treatment and suppression of cough, particularly for instances where respiratory examination, i.e. bronchoscopy, were to ensue, as such examination could be affected by a patient's cough (U.S. Pat. No. 6,362,197B1, JAOA, 98 (No 3): 170-172 (1998), Chest, 105:1592-93 (1994), JAMA, 252 (No 17) 2456-2457 (1984), J. Canadian Assoc. Radiol., 22: 199-200 (1971), Am. J. Emerg. Med., 19:206-207 (2001), Regional Anesthetics, 18:312-314 (1993), British J. Pharmacol., 138:407-416 (2003), J. Appl. Physiol., 74: 1419-1424 (1993).
All prior disclosures dealing with lidocaine inhalation have certain shortcomings in terms of safety and tolerability of inhaled lidocaine. Safety concerns associated with the administration of lidocaine are oropharyngeal numbing with loss of gag reflex, risk of aspiration of fluids and food, moderate to severe bronchospasm and taste problems. In addition, the previously described treatments use a large amount of lidocaine delivered slowly over long periods of time that are not efficient enough to provide increase in the tolerance and safety of the lungs for delivery of certain drugs by inhalation.
Attempts to use an aerosolized lidocaine prior to administration of aerosolized cyclosporine are described in Am. J. Respir. Crit. Care Med., 151: 516-521 (1995), Am. J. Respir. Crit. Care Med., 153: 1451-1455 (1996), and Am. J. Respir. Crit. Care Med., 155: 1690-1698 (1997). In all these publications, the described administration of cyclosporine is preceded by administration of 5 ml of 2%, that is 100 mg, of aerosolized lidocaine alone or in combination with the aerosolized albuterol using a conventional or Inspiron jet nebulizer. These pretreatments were given in order to minimize cough, pharyngeal soreness, and breathlessness. However, due to incorrectly designed cyclosporine aerosol and lidocaine treatment and due to use of the inefficient nebulizer, cough, pharyngeal soreness, and breathlessness were not sufficiently ameliorated and were repeatedly observed together with acute breathlessness following the aerosol cyclosporine administration. In addition, the type of nebulizers (conventional or jet nebulizers) will deliver only approximately 10% of the nominal dose to the lungs, and substantially more (>20-30%) to the oropharynx. As a consequence, the patients experience substantial numbing of mouth and throat, and regurgitation. In these studies, the efficacy of aerosolized cyclosporine, determined for example by FEV1 improvement, was clearly correlated with the amount of cyclosporine deposited in the lungs. The amount of the deposited cyclosporine has now been found to be directly dependent on the pretreatment with aerosolized lidocaine. In other words, aerosolized cyclosporine would not be effective without inhaled lidocaine pretreatment.
From a safety standpoint, it is extremely important for transplant patients to be protected from regurgitation and aspiration, as the lungs are denervated after the operation. For this reason, it is very important to provide a delivery of lidocaine to the lungs that does not impair the gag reflex or cause aspiration.
From the brief description of the problems encountered with an aerosolized drug delivery, it is clear that there is a continuous need for improvement of airway tolerance and airway deposition for therapeutically effective drugs delivered by aerosolization.
A method for such improvement of tolerance would preferably comprise a pretreatment step comprising inhalation of the aerosolized lidocaine or lidocaine-like compounds delivering a therapeutically effective amount of 10, 40 or 100 mg of lidocaine or lidocaine-like compounds in one ml of saline by aerosolization in particle sizes being substantially within either 2 and 5 or 3.5 and 10 microns directly to the lower lung or to the endobronchial space of airways, in a shortest possible time limited to at most 3 minutes with minimal oropharyngeal numbing and regurgitation.
It is, therefore, a primary object of this invention to provide a method for improved tolerance for delivery of the aerosolized primary therapeutically effective agent and for increased deposition of the aerosolized agent by providing a safe, physiologically acceptable and efficacious inhalable lidocaine or lidocaine-like compound for inhalation using a pure, preservative free lidocaine or lidocaine-like compound solution having pH between 5.5 and 7.5 which formulation contains a sufficient but not excessive concentration of lidocaine or lidocaine-like compound to improve the tolerance and drug deposition of the aerosolized therapeutically effective agent, that can be efficiently aerosolized by nebulization using an especially adapted and modified electronic nebulizer into an aerosol having an MMAD within a range from 0.1 to 2, 2 to 5 or 3.5 to 10 μm, with a substantially monodisperse particle distribution spectrum, or a dry powder formulation with similar aerosol properties administered with a dry powder inhaler, both well tolerated by patients.
All patents, patent applications and publications cited herein are hereby incorporated by reference.